To the Editor:
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis caused by an autoimmune inflammatory process with lymphocyte infiltration and fibrosis that lead to organ dysfunction,1 related to high levels of IgG4 and anti-carbonic anhydrase II antibodies.2,3 This disease frequently produces extra-pancreatic manifestations as well, such as sclerosing cholangitis and tubulointerstitial nephritis.4
Sclerosing cholangitis associated with AIP produces imaging test results and a clinical presentation similar to that of primary sclerosing cholangitis (PSC), but has a dramatic response to steroid treatment.5
Here, we describe the case of a patient with repeated episodes of pancreatitis and cholangitis who was managed as a case of PSC with no response, and who developed tubulointerstitial nephritis with renal biopsy findings suggestive of an autoimmune process, with resolution of gastrointestinal and renal manifestations through the administration of steroids.
CASE REPORT
Our patient was a 37-year old male who sought treatment in March 2006 for jaundice, fever, and abdominal pain; we first suspected an episode of cholangitis, but an endoscopic retrograde cholangiopancreatography and p-ANCA tests due to suspected PSC were negative, leading to the suspicion of microlithiasis.
In May of 2006, we performed an endoscopic sphincterotomy. Eight days later, the patient showed another episode of cholangitis. We considered the possibility of acalculous gallbladder disease as the cause for the recurring cholangitis; a cholecystokinin scintigraphy was compatible with this diagnosis, and we performed a laparoscopic cholecystectomy, but 15 days later the patient returned with yet another episode of cholangitis.
We returned to the suspected diagnosis of PSC, and performed a liver biopsy that revealed acute cholangitis with minimal foci of fibrosis. In early 2007, we administered a magnetic resonance cholangiography that revealed constrictions that were compatible with the diagnosis of PSC, with no possibility of performing a surgical intervention.
We managed the patient as a case of PSC, administering ursodeoxycholic acid and low doses of antibiotics (ciprofloxacin), and yet the patient continued to suffer repeated episodes of cholangitis.
In October 2007, the patient sought treatment for fever and abdominal pain; we started treatment with ciprofloxacin and requested an abdominal contrast tomography based on the patient’s creatinine value of 8.7mg/dl. In May 2007, the patient’s creatinine value was 1.2mg/dl.
The patient was evaluated in nephrology, and the only finding was paleness.
Laboratory analyses revealed creatinine: 7.6mg/dl, blood urea nitrogen (BUN): 46, normal sodium and potassium levels, pH: 7.32, bicarbonate: 16, Hb: 9.7g/dl, urinalysis with glycosuria (50mg/dl) and no hyperglycaemia.
A renal ultrasound revealed normally sized kidneys with increased bilateral echogenicity.
The patient was diagnosed with acute renal failure secondary to tubulointerstitial nephritis due to the consumption of quinolones.
After antibiotic treatment was removed and the patient was hydrated on the following day, creatinine decreased to 5.5mg/dl and BUN to 36mg/dl. Serum complement was normal, anti-nuclear antibodies (ANA) and serological tests for syphilis (VDRL) and human immunodeficiency virus (HIB) were negative; 24-hour proteinuria was 580mg. The patient was discharged with a creatinine value of 2.2mg/dl.
Twenty days later, the patient returned again for treatment for fever, diarrhoea, and oedema. Upon hospitalisation the patient had a creatinine value of 15mg/dl, potassium at 5.8mEq/l, and urine cytochemistry revealed leukocyturia, proteinuria (25mg/dl), glycosuria (50mg/dl), and haematuria (erythrocytes: 6 per field). A physical examination revealed no pathological findings. We considered this to be an exacerbation of the previous case of renal failure; due to the suspicion of tubulointerstitial nephritis, we started treatment with prednisone and took a renal biopsy.
The renal biopsy revealed: acute tubulointerstitial nephritis; immunofluorescence revealed: IgG ++ (interstitial), IgA and IgM +++ (interstitial), k and lambda chains: absent, C3: +++ peripheral, M and Bowman’s capsule, and absence of C1q. We interpreted these findings as histological changes corresponding to acute tubulointerstitial nephritis due to hypersensitivity to medications as opposed to autoimmune.
We continued to treat the patient with steroids, and upon discharge, creatinine was at 3.6mg/dl.
Since starting the patient on steroids, no further episodes of cholangitis or pancreatitis were produced, which led to the diagnosis of AIP with sclerosing cholangitis and tubulointerstitial nephritis as extra-pancreatic complications.
We did not measure IgG4 levels, since the patient had already received steroid treatment.
The first outpatient follow-up consultation revealed creatinine at 1.6mg/dl. The steroid treatment was progressively decreased, and the patient is currently on a regimen of 5mg prednisone every other day indefinitely. Follow-up measurements of creatinine revealed values ranging from 1.4mg/dl-1.7mg/dl.
The last follow-up session in December 2010 showed the patient’s creatinine value to be 1.43mg/dl, and no new episodes of cholangitis or pancreatitis have occurred.
DISCUSSION
In 1961, Starles made the first description of chronic pancreatitis with autoimmune manifestations; later, in 1995, this form of pancreatitis was labelled by Yoshida as “autoimmune pancreatitits”.6
Although the number of reports of this disease has recently increased, and some studies report a prevalence of 5% among patients with chronic pancreatitis, the true incidence of AIP remains unknown.7
AIP is frequently associated with rheumatoid arthritis, Sjögren’s syndrome, and inflammatory bowel disease; it is also common to encounter hypergammaglobulinaemia and elevated IgG4 levels, anti-carbonic anhydrase II, and lactoferrin auto-antibodies, which suggests an autoimmune disease, although its pathogenesis is still unkown.1-3
The extra-pancreatic autoimmune manifestations of AIP include sclerosing sialadenitis, retroperitoneal fibrosis, interstitial pneumonitis, sclerosing cholangitis, and tubulointerstitial nephritis.4,8
As regards sclerosing cholangitis associated with this type of pancreatitis, diagnosis is hindered by the fact that this condition shares many imaging test, cholangiography, and clinical findings with PSC; several authors have reported that the appearance of this disease in patients older than 60 years of age, with elevated levels of IgG4, and a dramatic response to steroid treatment all favour the diagnosis of AIP-associated sclerosing cholangitis as opposed to PSC.5
Various diagnostic criteria have been suggested for AIP; these include the revised Japan criteria, which place special emphasis on imaging test findings, the Mayo Clinic criteria (HISORT), which involve the use of histological, imaging test, and serology findings, as well as the manifestations in other organs and response to steroids, and the Italian criteria, which give greater importance to histological findings; however, no unified international consensus exists regarding which diagnostic criteria to use.9
As yet, few cases of tubulointerstitial nephritis have been reported in association with AIP; generally, these are observed in male patients older than 50 years of age, with mononuclear cell infiltrates that are positive for IgG4 in the renal interstitium, and with clinical and serological (decreased IgG4 levels) evidence of response to steroid treatment.8,10
Despite the lack of information regarding IgG4 levels in our patient, there were elements to suggest sclerosing cholangitis and tubulointerstitial nephritis associated with AIP: frequent episodes of cholangitis with magnetic resonance cholangiography findings that initially produced the suspicion of PSC, but the patient showed little response to normal treatment and had no auto-antibodies (p-ANCA, ANA), which are present in 85% of all patients with this pathology; this was supported by the repeated episodes of pancreatitis with evidence of diffuse growth of the pancreas, and resolution of symptoms through treatment with steroids.
The renal biopsy findings, specifically those from immunofluorescence testing, favoured the diagnosis of an autoimmune mechanism responsible for producing the tubulointerstitial nephritis observed in this patient.
Conflicts of interest
The authors state that they have no potential conflicts of interest related to the content of this article.
